GENETIC ANALYSES OF GENES IN PRESENILIN RELATED PATHWAYS

早老素相关通路基因的遗传分析

• 批准号: 7483171
• 负责人: RUDOLPH Emile TANZI
• 金额: $ 47.11万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483171
• 关键词: 19q; Affect; Age; Allosteric Regulation; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apolipoprotein E; Biological; Candidate Disease Gene; Catalysis; Categories; Chromosomes; Chromosomes, Human, Pair 19; Complex; Data; Evaluation; Family; Follow-Up Studies; Funding; Generations; Genes; Genetic; Genetic Transcription; Genome; Genomics; Haplotypes; Individual; Laboratories; Ligand Binding; Linkage Disequilibrium Mapping; Logistic Regressions; Methods; National Institute of Mental Health; Pathogenesis; Pathway interactions; Positioning Attribute; Post-Translational Protein Processing; Protein C; Proteins; RNA Splicing; Relative (related person); Resolution; Resources; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Survival Analysis; Testing; base; disorder risk; gamma secretase; genetic analysis; genetic linkage; genetic linkage analysis; novel; presenilin; secretase; signal peptide peptidase

In Project 2, we have shifted our focus to genetic analyses of positional candidate genes encoding proteins implicated in presenilin-related pathways. Over the past decade, our group has led the ascertainment, evaluation, and comprehensive genetic analyses of the NIMH Genetics Initiative Alzheimer's disease (AD) sample. This set of AD families, which currently includes 1527 individuals in 457 families, is the largest uniformly ascertained and evaluated sample ever assembled for the study of AD genetics. In separately funded studies, our laboratory recently completed the genetic analyses and preliminary follow-up studies of a comprehensive high-resolution genome screen for novel AD genes. The genome screen revealed that in addition to the expected highly significant linkage peak on chromosome 19q (APOE locus), several regions demonstrate evidence of 'suggestive' linkage to AD. In separately funded studies, we are further refining these linkage regions using additional markers. The immense data emanating from this screen constitute a powerful resource for research efforts aimed at identifying novel AD genes. To identify novel AD genes, we propose a positional candidate approach in which we test biologically compelling candidate genes from our AD genetic linkage peaks using family-based association, augmented by linkage disequilibrium mapping. Clusters of tightly spaced single nucleotide polymorphisms (SNPs) in positional candidate genes encoding proteins that are biologically implicated in presenilin-related pathways will be tested for association with AD. These genes have been divided into six categories: a. presenilin interactors, b. PS/gamma-secretase substrates, c. PS/gamma-secretase complex components and proteins that affect PS/gamma-secretase activity/Abeta generation, d. amyloid precursor protein (APP) C-terminus/APP intracellular domain (AICD) interactors, e. AICD transcriptional targets, and f. presenilin-like signal peptide peptidases. Testing of these genes will be prioritized according to their genomic position relative to the best-confirmed AD genetic linkage peaks, and their biological relevance to AD pathogenesis. Candidate genes for which positive signals are successfully found in the NIMH sample will be tested in an independent sample, the Consortium on Alzheimer's Genetics (CAG) sample. SNPs found to be strongly associated with AD in these samples will be phenotypically and functionally characterized including collaborative analyses with the six other PPG laboratories.

在项目2中，我们将重点转移到早老素相关途径中编码蛋白的位置候选基因的遗传分析上。在过去的十年中，我们的团队领导了NIMH遗传倡议阿尔茨海默病（AD）样本的确定、评估和综合遗传分析。这组阿尔茨海默病家族，目前包括457个家族的1527个个体，是迄今为止为阿尔茨海默病遗传学研究收集的最大的统一确定和评估样本。在单独资助的研究中，我们的实验室最近完成了a的基因分析和初步随访研究